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Differences in hepatic cytochrome P450 activity correlate with the strain-specific biotransformation of medetomidine in AX/JU and IIIVO/JU inbred rabbits

Authors

  • H. AVSAROGLU,

    1. Central Laboratory Animal Institute, Utrecht University, Utrecht, The Netherlands
    2. Laboratory Animal Science Division, Department of Animals, Science & Society, Utrecht University, Utrecht, The Netherlands
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  • S. BULL,

    1. Chemical Hazards & Poisons Division, Centre for Radiation, Chemical & Environmental Hazards, Health Protection Agency, Chilton, UK
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  • R. F. MAAS-BAKKER,

    1. Division Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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  • P. SCHERPENISSE,

    1. Division Veterinary Public Health, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
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  • H. A. VAN LITH,

    1. Laboratory Animal Science Division, Department of Animals, Science & Society, Utrecht University, Utrecht, The Netherlands
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  • A. A. BERGWERFF,

    1. Division Veterinary Public Health, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
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  • L. J. HELLEBREKERS,

    1. Department of Equine Sciences & Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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  • L. F. M. VAN ZUTPHEN,

    1. Laboratory Animal Science Division, Department of Animals, Science & Society, Utrecht University, Utrecht, The Netherlands
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  • J. FINK-GREMMELS

    1. Division Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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H. Avsaroglu DVM, Central Laboratory Animal Institute, Utrecht University, P.O. Box 80190, 3508 TD Utrecht, The Netherlands. E-mail: h.avsaroglu@gdl.uu.nl

Abstract

Medetomidine is an α2-adrenoceptor agonist with sedative and analgesic properties. Previously we demonstrated significant differences in the response to medetomidine between two inbred rabbit strains, denoted IIIVO/JU and AX/JU. The aim of the present study was twofold: first, to compare the hepatic CYP450 enzyme activities between these rabbit strains [= 13(6♂♂,7♀♀)/strain]. To this end, liver microsomes were incubated with known fluorescent substrates for the major drug-metabolizing CYP450 isoforms. A comparison of the obtained results indicated significant gender differences as well as differences between the two rabbit inbred strains. Secondly, the biotransformation rate of medetomidine in liver microsomes of both rabbit strains was determined using liquid chromatography coupled to tandem mass spectrometry. The rate of hydroxymedetomidine and medetomidine carboxylic acid formation was found to be significantly higher in the AX/JU strain. Specific CYP2D and CYP2E inhibitors could decrease the formation of both metabolites. Significant correlations were found between the rate of biotransformation of medetomidine and the activities of CYP2D and CYP2E, as well as between CYP450 enzyme activities and the anaesthetic response to medetomidine.

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